A calcium- and calpain-dependent pathway determines the response to lenalidomide in myelodysplastic syndromes
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Despite the high response rates of individuals with myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) to treatment with lenalidomide (LEN) and the recent identification of cereblon (CRBN) as the molecular target of LEN, the cellular mechanism by which LEN eliminates MDS clones remains elusive. Here we performed an RNA interference screen to delineate gene regulatory networks that mediate LEN responsiveness in an MDS cell line, MDSL. We identified GPR68, which encodes a G-protein-coupled receptor that has been implicated in calcium metabolism, as the top candidate gene for modulating sensitivity to LEN. LEN induced GPR68 expression via IKAROS family zinc finger 1 (IKZF1), resulting in increased cytosolic calcium levels and activation of a calcium-dependent calpain, CAPN1, which were requisite steps for induction of apoptosis in MDS cells and in acute myeloid leukemia (AML) cells. In contrast, deletion of GPR68 or inhibition of calcium and calpain activation suppressed LEN-induced cytotoxicity. Moreover, expression of calpastatin (CAST), an endogenous CAPN1 inhibitor that is encoded by a gene (CAST) deleted in del(5q) MDS, correlated with LEN responsiveness in patients with del(5q) MDS. Depletion of CAST restored responsiveness of LEN-resistant non-del(5q) MDS cells and AML cells, providing an explanation for the superior responses of patients with del(5q) MDS to LEN treatment. Our study describes a cellular mechanism by which LEN, acting through CRBN and IKZF1, has cytotoxic effects in MDS and AML that depend on a calcium- and calpain-dependent pathway.
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Lenalidomide monotherapy has produced CR rates of almost 20% in the settings of both newly diagnosed and R/R AML.
“Lenalidomide monotherapy has produced CR rates of almost 20% in the settings of both newly diagnosed and R/R AML102,103.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [103]
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- Authors
- Fang, J., Liu, X., Bolanos, L., Barker, B., Rigolino, C., Cortelezzi, A., Oliva, E. N., Cuzzola, M., Grimes, H. L., Fontanillo, C., Komurov, K., MacBeth, K., & Starczynowski, D. T.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Azienda ospedaliera "Bianchi-Melacrino-Morelli" (IT)
- University of Milan (IT)
- Corresponding author
- Starczynowski, Daniel T
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-06-13
- Volume
- 22
- Issue
- 7
- Pages
- 727-734
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5507589
- OpenAlex
- W2429225077
- Cited by
- 83
- References
- 37
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 7 · 2023: 8 · 2022: 9 · 2021: 12 · 2020: 15 · 2019: 5 · 2018: 10 · 2017: 7 · 2016: 3
- FWCI
- 7.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL114582, R01HL111103)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK090971)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Calpain Protease Function and Regulation
- Keywords
- lenalidomide, myelodysplastic syndrome, del(5q), cereblon, GPR68, G protein-coupled receptors, calcium signaling, calpain, calpain-1, calpastatin, IKZF1, apoptosis, acute myeloid leukemia, lenalidomide resistance, gene regulatory networks
- MeSH terms
- Lenalidomide, Calcium, Calcium-Binding Proteins, Calpain, Humans, Immunologic Factors, Myelodysplastic Syndromes, Peptide Hydrolases, Thalidomide, Leukemia, Myeloid, Acute, Gene Expression Regulation, Neoplastic, Apoptosis, RNA Interference, Receptors, G-Protein-Coupled, Ubiquitin-Protein Ligases, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Ikaros Transcription Factor, Gene Regulatory Networks
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